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Abstract
Pancreatic β-cell failure in type 2 diabetes mellitus is a serious challenge that results in an inability of the pancreas to produce sufficient insulin to properly regulate blood glucose levels. Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor expressed by β-cells that has recently been proposed as a potential target for improving glycemic control and suppressing binge eating behaviors. We discovered that TAAR1 is coupled to Gαs-signaling pathways in insulin-secreting β-cells to cause protein kinase A (PKA)/exchange protein activated by cAMP (Epac)-dependent release of insulin, activation of RAF proto-oncogene, Ser/Thr kinase (Raf)-mitogen-activated protein kinase (MAPK) signaling, induction of cAMP response element-binding protein (CREB)-insulin receptor substrate 2 (Irs-2), and increased β-cell proliferation. Interestingly, TAAR1 triggered cAMP-mediated calcium influx and release from internal stores, both of which were required for activation of a MAPK cascade utilizing calmodulin-dependent protein kinase II (CaMKII), Raf, and MAPK/ERK kinase 1/2 (MEK1/2). Together, these data identify TAAR1/Gαs-mediated signaling pathways that promote insulin secretion, improved β-cell function and proliferation, and highlight TAAR1 as a promising new target for improving β-cell health in type 2 diabetes mellitus.
Highlights
Pancreatic -cell failure in type 2 diabetes mellitus is a serious challenge that results in an inability of the pancreas to produce sufficient insulin to properly regulate blood glucose levels
We discovered that Trace amine–associated receptor 1 (TAAR1) is coupled to G␣s-signaling pathways in insulin-secreting -cells to cause protein kinase A (PKA)/exchange protein activated by cAMP (Epac)– dependent release of insulin, activation of RAF proto-oncogene, Ser/Thr kinase (Raf)–mitogen-activated protein kinase (MAPK) signaling, induction of cAMP response element– binding protein (CREB)–insulin receptor substrate 2 (Irs-2), and increased -cell proliferation
TAAR1 potentiates glucose-stimulated insulin secretion through cAMP-PKA and Epac-dependent signaling in pancreatic -cells
Summary
Trace amine–associated receptor 1 (TAAR1) promotes anti-diabetic signaling in insulin-secreting cells. TAAR1 triggered cAMP-mediated calcium influx and release from internal stores, both of which were required for activation of a MAPK cascade utilizing calmodulin-dependent protein kinase II (CaMKII), Raf, and MAPK/ERK kinase 1/2 (MEK1/2) Together, these data identify TAAR1/G␣s-mediated signaling pathways that promote insulin secretion, improved cell function and proliferation, and highlight TAAR1 as a promising new target for improving -cell health in type 2 diabetes mellitus. The molecular mechanisms by which TAAR1 directly regulates insulin secretion in -cells are largely unknown, as TAAR1 plays additional roles in gut motility, satiety, and eating behaviors [9, 10] Amine agonists such as octopamine, -phenylethylamine, tyramine, and amphetamines [11] exhibit neurotransmitter-like activity, and TAAR1 is expressed in the brain, where it has been shown to decrease binge eating behaviors and stimulate weight loss [9, 10]. We delineate the downstream effectors of TAAR1 in pancreatic -cell lines and provide evidence that TAAR1 agonists trigger beneficial anti-diabetic signaling pathways that could help lead to their use as anti-diabetic agents
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